Test if antitumor T cells use a putative super-enhancer in the Il1rl2-Il1rl1 intergenic region to form "innate-like" responses to cytokines
测试抗肿瘤 T 细胞是否使用 Il1rl2-Il1rl1 基因间区域中的假定超级增强子对细胞因子形成“先天样”反应
基本信息
- 批准号:9585298
- 负责人:
- 金额:$ 19.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-05-04 至 2020-04-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAffinityAgonistAntigen ReceptorsAntigensAvidityBindingBinding SitesBioinformaticsBypassCD8-Positive T-LymphocytesCancer PatientCardiovascular DiseasesCell physiologyCellsChIP-seqChromatinChromatin LoopCollaborationsConsensusCytotoxic T-Lymphocyte-Associated Protein 4DataData SetElementsEnhancersEpitopesFamilyFamily memberFoundationsFundingFutureGenerationsGenesGenomicsHigh-Throughput Nucleotide SequencingImmuneImmune checkpoint inhibitorImmunosuppressive AgentsImmunotherapeutic agentInflammationIntercistronic RegionInterferon Type IIInterleukin-1Interleukin-12Interleukin-18Interleukin-2JointsMalignant NeoplasmsMediatingMessenger RNAModelingMolecularMusNatural Killer CellsPDCD1LG1 genePathway interactionsProcessPublicationsPublishingRNA Polymerase IIResearchRoleScheduleScienceSiteStat5 proteinT cell responseT-Cell ActivationT-LymphocyteTestingTherapeuticTumor AntigensTumor ImmunityWorkanti-PD-1basecancer immunotherapycancer therapycell killingcell motilitychromatin immunoprecipitationchromosome conformation capturecytokineexperiencegenome editingimmune functionmeetingsmemberneoplastic cellnovelpatient subsetsprogramspromoterreceptor functionresponsetreatment responsetumortumor growthtumor microenvironment
项目摘要
Project Summary
The new generation of T cell-based cancer immunotherapeutics, best exemplified by the checkpoint inhibitors
anti-CTLA-4 and anti-PD-1/PD-L1, can elicit therapeutic antitumor immunity in cancer patients. Nevertheless,
these therapeutic responses are often not durable or only experienced in a subset of patients, likely owing to a
variety of immunosuppressive mechanisms employed by tumors to subvert the action of antitumor T cells. For
instance, T cells expressing antigen receptors (TCRs) that recognize MHC restricted-tumor epitopes with high
avidity/affinity have a propensity to undergo functional inactivation or deletion, and hence cytolytic effector T
cells (CTL) localized within tumors generally have a limited ability to recognize and be triggered by tumor
epitopes. Hence, strategies to amplify weak tumor epitope recognition, or even induce TCR-independent T cell
activation intratumorally, might boost T cell-mediated antitumor efficacy. In this regard, we previously found
that effector T cells programmed with antitumor promoting costimulatory agonists can be triggered to
degranulate and secrete the tumoricidal cytokine IFN-γ through a TCR-independent process that involves
stimulation with a STAT-activating cytokine (IL-2 or IL-12) plus an IL-1 family member (IL-33 or IL-36). This
“innate-like” response is akin to how innate immune cells such as NK cells can be triggered through cytokine
combinations such as IL-12 plus IL-18, and may help explain why the presence of IL-36 in the tumor
microenvironment limits tumor growth. Further, engaging this 2-cytokine triggering pathway will be an effective
means to boost the efficacy of cancer immunotherapies. In analyzing the mechanism of this 2-cytokine
pathway using costimulated CD8+ T cells treated with the IL-2 + IL-36 combination, it was found that IL-2
primes for IL-36 responsiveness by rapidly inducing IL-36R mRNA (encoded by the Il1rl2 gene) in a
JAK/STAT-dependent manner. Chromatin immunoprecipitation with high throughput sequencing (ChIP-seq)
revealed that IL-2 induces STAT5 binding to five separate STAT/GAS consensus elements located throughout
a large ~75 kb intergenic region between Il1rl2 and Il1rl1 (encoding IL-33R that is also induced by IL-2).
Strikingly, RNA polymerase II bound the same sites prior to IL-2 stimulation. These results, in concert with a
previous bioinformatic analysis of publically available ChIP-seq data sets generated from IFN-γ-expressing T
cells, forms the basis of the novel overarching hypothesis that will be tested in this project that the Il1rl2-Il1rl1
intergenic region contains a super-enhancer (SE) that serves as a molecular hub to facilitate cross-talk
between STAT-activating and IL-1 family cytokines during “innate-like” antitumor T cell responses.
项目摘要
新一代基于T细胞的癌症免疫治疗,最好的例子是检查点抑制剂
抗-CTLA-4和抗-PD-1/PD-L1,可以在癌症患者中引发治疗性抗肿瘤免疫。然而,尽管如此,
这些治疗反应通常不持久或仅在一部分患者中经历,可能是由于
肿瘤采用多种免疫抑制机制来破坏抗肿瘤T细胞的作用。为
例如,表达抗原受体(TCR)的T细胞,其识别具有高表达的MHC限制性肿瘤表位。
亲合力/亲和力具有经历功能失活或缺失的倾向,因此溶细胞效应物T
位于肿瘤内的细胞(CTL)通常具有有限的识别肿瘤和被肿瘤触发的能力,
表位因此,扩增弱肿瘤表位识别,或甚至诱导TCR非依赖性T细胞增殖的策略,
肿瘤内激活,可能会增强T细胞介导的抗肿瘤功效。在这方面,我们以前发现,
用抗肿瘤促进共刺激激动剂编程的效应T细胞可以被触发,
通过TCR非依赖性过程去分化和分泌杀肿瘤细胞因子IFN-γ,
用STAT激活细胞因子(IL-2或IL-12)加IL-1家族成员(IL-33或IL-36)刺激。这
“先天样”反应类似于先天免疫细胞如NK细胞如何通过细胞因子激活而被触发。
IL-12加IL-18的组合,并可能有助于解释为什么IL-36在肿瘤中的存在
微环境限制肿瘤生长。此外,参与这种2-细胞因子触发途径将是有效的
提高癌症免疫治疗效果的方法。在分析这种2-细胞因子的机制时,
使用用IL-2 + IL-36组合处理的共刺激的CD 8 + T细胞,发现IL-2
通过快速诱导IL-36 R mRNA(由Il 1 rl 2基因编码)在细胞中表达,
JAK/STAT依赖方式。染色质免疫沉淀与高通量测序(ChIP-seq)
揭示IL-2诱导STAT 5与位于整个细胞中的五个单独的STAT/GAS共有元件结合,
在Il 1 rl 2和Il 1 rl 1之间的大的~75 kb基因间区域(编码也由IL-2诱导的IL-33 R)。
引人注目的是,RNA聚合酶II在IL-2刺激之前结合相同的位点。这些结果,与一个
对从表达IFN-γ的T细胞产生的可生物学获得的ChIP-seq数据集的先前生物信息学分析
细胞,形成了新的总体假设的基础,将在本项目中进行测试,即Il 1 rl 2-Il 1 rl 1
基因间区域包含一个超级增强子(SE),作为一个分子枢纽,以促进串扰
STAT激活和IL-1家族细胞因子在“先天性”抗肿瘤T细胞应答中的作用。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('ADAM J ADLER', 18)}}的其他基金
Generating a novel conditional knockout mouse for a super-enhancer that controls cytokine responsiveness
生成一种新型条件敲除小鼠,用于控制细胞因子反应的超级增强子
- 批准号:
10740932 - 财政年份:2023
- 资助金额:
$ 19.94万 - 项目类别:
Understanding how the interaction between Lag3 deficiency and hypercholesterolemia impact anti-tumor immunity and cardiovascular disease in a melanoma model
了解 Lag3 缺乏与高胆固醇血症之间的相互作用如何影响黑色素瘤模型中的抗肿瘤免疫和心血管疾病
- 批准号:
10637369 - 财政年份:2023
- 资助金额:
$ 19.94万 - 项目类别:
Breaking Tolerance to Induce Tumor-Specific Cytotoxic CD4 Th1 Cells
打破耐受性以诱导肿瘤特异性细胞毒性 CD4 Th1 细胞
- 批准号:
8292553 - 财政年份:2012
- 资助金额:
$ 19.94万 - 项目类别:
Breaking Tolerance to Induce Tumor-Specific Cytotoxic CD4 Th1 Cells
打破耐受性以诱导肿瘤特异性细胞毒性 CD4 Th1 细胞
- 批准号:
8785648 - 财政年份:2012
- 资助金额:
$ 19.94万 - 项目类别:
Breaking Tolerance to Induce Tumor-Specific Cytotoxic CD4 Th1 Cells
打破耐受性以诱导肿瘤特异性细胞毒性 CD4 Th1 细胞
- 批准号:
8424214 - 财政年份:2012
- 资助金额:
$ 19.94万 - 项目类别:
Redirecting T Cell Responses to Self/Tumor Antigens Using Enforced Costimulation
使用强制共刺激重定向 T 细胞对自身/肿瘤抗原的反应
- 批准号:
8436254 - 财政年份:2004
- 资助金额:
$ 19.94万 - 项目类别:
Redirecting T Cell Responses to Self/Tumor Antigens Using Enforced Costimulation
使用强制共刺激重定向 T 细胞对自身/肿瘤抗原的反应
- 批准号:
8792152 - 财政年份:2004
- 资助金额:
$ 19.94万 - 项目类别:
Redirecting T Cell Responses to Self/Tumor Antigens Using Enforced Costimulation
使用强制共刺激重定向 T 细胞对自身/肿瘤抗原的反应
- 批准号:
7800669 - 财政年份:2004
- 资助金额:
$ 19.94万 - 项目类别:
Redirecting T Cell Responses to Self/Tumor Antigens Using Enforced Costimulation
使用强制共刺激重定向 T 细胞对自身/肿瘤抗原的反应
- 批准号:
7994197 - 财政年份:2004
- 资助金额:
$ 19.94万 - 项目类别:
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